List of Phenyltropanes
Encyclopedia
Such list of phenyltropane
Phenyltropane
Phenyltropanes were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these...

s
present many different avenues of research into therapeutic and addiction control depending on their construction and structure-activity relationship
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...

 ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 & Parkinson's
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

 diseases. More recently there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of being among one kind that would make it among others of this substance profile.

2-Carboxymethyl esters

Certain phenyltropanes can be used as a smoking cessation aid.

Selected Phenyltropanes
Short Name X DA 5HT NE
WIN 35,065-2 (CPT) H 23 1962 920
WIN 35,428 (CFT) F 14 156 85
RTI-29  NH2 9.8 5110 151
RTI-31
RTI-31
-2β-Carbomethoxy-3β-tropane is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit...

 
Cl 1.12 44.5 37
RTI-32
RTI-32
-2β-Carbomethoxy-3β-tropane is a phenyltropane-based cocaine analog that is important in the field of medicinal chemistry for performing SAR.It has similar properties in vitro to related drugs such as RTI-31....

 
Me 1.71 240 60
RTI-51
RTI-51
-2β-Carbomethoxy-3β-tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and...

 
Br 1.69 10.6 37.4
Iometopane (RTI-55) I 1.26 4.21 36
RTI-83
RTI-83
-2β-Carbomethoxy-3β-tropane is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related...

Et 55 28 4030
RTI-298 –≡–Ph 3.7 46.8 347
RTI-436 –CH=CHPh 3.09 335 (31) 1960 (1181)
RTI-430 –C≡C(CH2)2Ph 6.28 2128 (198) 1470 (886)

(3,4-Disubstituted phenyl)-tropanes

Compound X Y 2 Position config 8 DA 5-HT NE
RTI-318  β-naphthyl CO2Me β,β NMe 0.5 0.81 20
Dichloropane (RTI-111) Cl Cl CO2Me β,β NMe 0.79 3.13 18.0
RTI-88 [recheck] NH2 I CO2Me β,β NMe 1.35 1329 320
RTI-97  NH2 Br CO2Me β,β NMe 3.91 181 282
RTI-112
RTI-112
RTI-112 is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113 which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor....

 
Cl Me CO2Me β,β NMe 0.82 10.5 36.2
RTI-96  F Me CO2Me β,β NMe 2.95 76 520
RTI-295  Et I CO2Me β,β NMe 21.3 2.96 1349
RTI-353
RTI-353
RTI-353 is a phenyltropane derived drug which acts as an SSRI....

 (EINT)
Et I CO2Me β,β NH 331 0.69 148
RTI-279  Me I CO2Me β,β NH 5.98 1.06 74.3
RTI-280  Me I CO2Me β,β NMe 3.12 6.81 484

Arylcarboxy

2Ph> 2Ph > 2Ph > 2Ph > 2(p-C6H4I)> 2(o-C6H4Me)> 2(m-C6H4Me)> 2(p-C6H4Me)>
Compound X 2 Position config 8 DA 5-HT NE
RTI-122  I
β,β NMe 1.50 184 3,791
RTI-113
RTI-113
RTI-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor . It has been suggested as a possible substitute drug for the treatment of cocaine addiction...

 
Cl
β,β NMe 1.98 2,336 2,955
RTI-277  NO2
β,β NMe 5.94 2,910 5,695
RTI-120
RTI-120
-2β-Carbophenoxy-3β-tropane is a phenyltropane derivative which acts as a reasonably selective dopamine reuptake inhibitor, along with weaker inhibition of noradrenaline and serotonin reuptake. It has a reasonably fast rate of occupancy of dopamine transporters in the brain, though slower than...

 [recheck]
Me
β,β NMe 3.26 24,471 5,833
RTI-116  Cl
β,β NMe 33 1,227 968
RTI-203  Cl CO2(m-C6H4Me) β,β NMe 9.37 2153 2744
RTI-204  Cl
β,β NMe 3.91 3,772 4,783
RTI-205  Me
β,β NMe 8.19 5,237 2,137
RTI-206 Cl
β,β NMe 27.4 1,203 1,278

Carboxyalkyl

2Pri> 2Pri> 2Prcyc> 2Pri> 2Pri > 2Prcyc> 2Prcyc> 2Pri> 2Bucyc> 2C(H)Et2> 2CH2Ph>
Code X 2 Position config 8 DA 5-HT NE
RTI-77 Cl CH2CH2(3-iodo-p-anilino) β,β NMe 2.51 2247
RTI-121
RTI-121
-2β-Carboisopropoxy-3β-tropane is a stimulant drug used in scientific research, which was developed in the early 1990s. RTI-121 is a phenyltropane based, highly selective dopamine reuptake inhibitor and is derived from methylecgonidine...

 
I
β,β NMe 0.43 66.8 285
RTI-153  I
β,β NH 1.06 3.59 132
RTI-191  I
β,β NMe 0.61 15.5 102
RTI-114  Cl
β,β NMe 1.40 1,404 778
RTI-278  NO2
β,β NMe 8.14 2,147 4,095
RTI-190  Cl
β,β NMe 0.96 168 235
RTI-193  Me
β,β NMe 1.68 1,066 644
RTI-117  Me
β,β NMe 6.45 6,090 1,926
RTI-150  Me
β,β NMe 3.74 2,020 4,738
RTI-127  Me
β,β NMe 19 4500 3444
RTI-338 ethyl
β,β NMe 1104 7.41 3366

Use of a cyclopropyl ester appears to enable better MAT
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...

 retention than does the choice of isopropyl
Isopropyl
In organic chemistry, isopropyl is a propyl with a group attached to the secondary carbon. If viewed as a functional group an isopropyl is an organic compound with a propyl group attached at its secondary carbon.The bond is therefore on the middle carbon....

 ester.

Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.

Amides

RTI-183 and RTI-218 have the same structure??
Code X 2 Position config 8 DA NE 5-HT
RTI-106  Cl CON(H)Me β,β NMe 12.4 1511 1312
RTI-118  Cl CONH2 β,β NMe 11.5 4267 1621
RTI-222 Me morpholinyl β,β NMe 11.7 >100K
RTI-129  Cl CONMe2 β,β NMe 1.38 942 1079
RTI-146  Cl CONHCH2OH β,β NMe 2.05 144 98
RTI-147  Cl CON(CH2)4 β,β NMe 1.38 3,949 12,394
RTI-156  Cl CON(CH2)5 β,β NMe 6.61 5832 3468
RTI-170  Cl CON(H)CH2C≡CH β,β NMe 16.5 1839 4827
RTI-172  Cl CON(H)NH2 β,β NMe 44.1 3914 3815
RTI-174  Cl CONHCOMe β,β NMe 158 >43K >125K
RTI-182  Cl CONHCH2COPh β,β NMe 7.79 1722 827
RTI-183  Cl CON(OMe)Me β,β NMe 0.85 549 724
RTI-186  Me CON(OMe)Me β,β NMe 2.55 442 (266) 3400 (309)
RTI-198  Cl CON(CH2)3 β,β NMe 6.57 990 813
RTI-196  Cl CONHOMe β,β NMe 10.7 9907 >43K
RTI-201  Cl CONHNHCOPh β,β NMe 91.8 >20K >48K
RTI-208  Cl CONO(CH2)3 β,β NMe 1.47 998 2470
RTI-214  Cl CON(-CH2CH2-)2O β,β NMe 2.90 8545 >88K
RTI-215  Cl CONEt2 β,β NMe 5.48 ? 9432
RTI-217  Cl CONH(m-C6H4OH) β,β NMe 4.78 >30K >16K
RTI-218  Cl CON(Me)OMe β,β NMe 1.19 520 1911
RTI-226  Cl CONMePh β,β NMe 45.0 ? 24K
RTI-227  I CONO(CH2)3 β,β NMe 0.75 446 230
RTI-229
RTI-229
-3β-tropane-2β-pyrrolidine carboxamide is a potent and long-lasting stimulant drug which was developed in the 1990s as part of a large group of related analogues from the phenyltropane family...

 
I CON(CH2)4 β,β NMe 0.37 991 1,728

Acyl

i >
Code X Y 2 Position config 8 DA 5-HT NE
WF-23 β-naphthyl C(O)Et β,β NMe 0.115 0.394 No data
WF-31
2-Propanoyl-3-(4-isopropylphenyl)-tropane
2-Propanoyl-3--tropane is a cocaine analogue. Research shows WF-31 to be approximately ten times more potent than cocaine at binding to serotonin and at inhibiting serotonin uptake.- References :...

 
H C.O.Et β,β NMe 615 54.5 No data
WF-11  Me H
β,β NMe 8.2 131 No data
WF-25 H H
β,β NMe 48.3 1005 No data
WF-33  6-MeoBN C(O)Et α,β NMe 0.13 2.24 No data

Ester reduction

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methylcarbonate
Carbonate
In chemistry, a carbonate is a salt of carbonic acid, characterized by the presence of the carbonate ion, . The name may also mean an ester of carbonic acid, an organic compound containing the carbonate group C2....

.

2OH > 2OH > 2OH > 2OH > 2OAc > 2OBz > 2OCO2Me>
Code X 2 Position config 8 DA 5-HT NE
RTI-100  F
β,β NMe 47 4741 no data
RTI-101  I
β,β NMe 2.2 26 no data
RTI-99  Br
β,β NMe 1.49 51 no data
RTI-93  Cl
β,β NMe 1.53 204 43.8
RTI-105  Cl
β,β NMe 1.60 143 127
RTI-123  Cl
β,β NMe 1.78 3.53 393
RTI-145 Cl
β,β NMe 9.60 2.93 1.48

Misc.

2Cl > 2CO2Me> 3> 2> 2OCO2Me> 2NH2> 2NHMe> 2NMe2> 2> 2CH2Ph>
Code X 2 Position config 8 DA 5-HT NE
RTI-102 I CO2H β,β NMe 474 1928 43,400
RTI-103 Br CO2H β,β NMe 278 3070 17,400
RTI-104 F CO2H β,β NMe 2744 >100K >100K
RTI-108  Cl
β,β NMe 2.64 98 129.8
RTI-241  Me
β,β NMe 1.02 619 124
RTI-139  Cl
β,β NMe 1.67 85 57
RTI-161  Cl
β,β NMe 13.1 1887 2516
RTI-230  Cl H3C–Ç=CH2 β,β NMe 1.28 57 141
RTI-240  Cl
β,β NMe 1.38 38.4 84.5
RTI-145 Cl
β,β NMe 9.60 2,932 1,478
RTI-158  Me
β,β NMe 57 5095 1624
RTI-131  Me
β,β NMe 10.5 855 120
RTI-164  Me
β,β NMe 13.6 2246 280
RTI-132  Me
β,β NMe 3.48 206 137
RTI-239  Me
β,β NMe 0.61 114 35.6
RTI-338  Et
β,β NMe 1104 7.41 3366
RTI-348  H
β,β NMe 28.2 >34,000 2670

F&B series

The compound of the present invention are useful pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...

s.
Code X 2 Position config DA NE 5-HT
RTI-224  Me F1c β,β 4.49 155.6
RTI-233  Me F2 β,β 4.38 516 73.6
RTI-235  Me F3 d β,β 1.75 402 72.4
RTI-236  Me B1 d β,β 1.63 86.8 138
RTI-237  Me B2 d β,β 7.27 258 363
RTI-244  Me B3 d β,β 15.6 1809 33.7
RTI-245  Cl F4 c β,β 77.3
RTI-246  Me F4 c β,β 50.3 3000
RTI-248  Cl F6 c β,β 9.73 4674 6.96
RTI-249  Cl F1 c β,β 8.32 5023 81.6
RTI-266  Me F2 β,β 4.80 836 842
RTI-267  Me F7 wrong β,β 2.52 324 455
RTI-268  Me F7 right β,β 3.89 1014 382
RTI-269  Me F8 β,β 5.55 788 986

Biotin
Biotin
Biotin, also known as Vitamin H or Coenzyme R, is a water-soluble B-complex vitamin discovered by Bateman in 1916. It is composed of a ureido ring fused with a tetrahydrothiophene ring. A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring...


β,α Stereochemistry

Compound X 2 Group config 8 DA 5-HT NE
RTI-140 H CO2Me β,α NMe 101 5,701 2,076
RTI-352
RTI-352
RTI-352 is a phenyltropane that is used as a radiolabeling ligand for the DAT. RTI-352 has been configured to have 1R,2S,3R stereochemistry and is therefore a geometric isomer of β-CIT....

 
I CO2Me β,α NMe 2.86 64.9 52.4
RTI-549  Br CO2Me β,α NMe
RTI-319  BN CO2Me β,α NMe 1.1 11.4 70.2
RTI-286  F CO2Me β,α NMe 21 5062 1231
RTI-274
RTI-274
RTI-274, or 2β--3α-nortropane is a phenyltropane homologue of paroxetine developed by the group led by F Ivy Carroll in the 1990s.-Introduction:...

 
F CH2O(3'4'-MD-phenyl) β,α NH 3.96 5.62 14.4
RTI-287  Et CO2Me β,α NMe 327 1687 17,819

α,β Stereochemistry

{| class="wikitable"
| Compound || X || 2 Group || config || 8 || DA||5-HT||NE
|-
| Brasofensine
Brasofensine
Brasofensine is a phenyltropane that had been under development for the treatment of Parkinson's and Alzheimer's disease...

 || Cl2 || methyl aldoxime || α,β || NMe || ||||
|-
| Tesofensine
Tesofensine
Tesofensine is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity...

 || Cl2 || ethoxymethyl || α,β || NMe ||65||11||1.7
|-
|NS-2359 (GSK-372,475)|| Cl2 || Methoxymethyl || α,β || NH || || ||
|}

Heterocycles

These heterocycles are sometimes referred to as the "bioisosteric
Bioisostere
In medicinal chemistry, bioisosteres are substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to a chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or...

 equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize to the energetically more favorable trans configuration. This can also happen to cocaine also.

3-Substituted-isoxazol-5-yl

N-methylphenyltropanes with 1R β,β stereochemistry.
Code X R DA NE 5HT
RTI-165  Cl 3-methylisoxazol-5-yl 0.59 181 572
RTI-171
RTI-171
-2β--3β-tropane is a phenyltropane derivative which acts as a selective dopamine reuptake inhibitor, with a relatively slow onset of action and short duration of effects found in animal studies....

 
Me 3-methylisoxazol-5-yl 0.93 254 3818
RTI-180  I 3-methylisoxazol-5-yl 0.73 67.9 36.4
RTI-177
RTI-177
RTI-177 is a synthetic stimulant drug from the phenyltropane family, which acts as a DRI with micromolar affinity for the SERT...

 
Cl 3-phenylisoxazol-5-yl 1.28 504 2418
RTI-176  Me 3-phenylisoxazol-5-yl 1.58 398 5110
RTI-181  I 3-phenylisoxazol-5-yl 2.57 868 100
RTI-184  H methyl 43.3 6208
RTI-185  H Ph 285 >12K
RTI-334  Cl 3-ethylisoxazol-5-yl 0.50 120 3086
RTI-335  Cl isopropyl 1.19 954 2318
RTI-336  Cl 3-(4-methylphenyl)isoxazol-5-yl 4.09 1714 5741
RTI-337  Cl 3-t-butyl-isoxazol-5-yl 7.31 6321 37K
RTI-345  Cl p-chlorophenyl 6.42 5290 >76K
RTI-346  Cl p-anisoyl 1.57 762 5880
RTI-347  Cl p-fluorophenyl 1.86 918 7257
RTI-354 Me 3-ethylisoxazol-5-yl 1.62 299 6400
RTI-366 Me R = isopropyl 4.5 2523 (1550) 42,900 (3900)
RTI-371
RTI-371
3β--2β-[3-isoxazol-5-yl]tropane is a phenyltropane derived drug which acts as a potent and selective dopamine reuptake inhibitor in vitro, yet unusually for this class of compound, both RTI-371 and the closely related compound RTI-370 failed to produce locomotor stimulation in mice...

Me p-chlorophenyl 8.74 >100K (60,200) >100K (9090)
RTI-386 Me p-anisoyl 3.93 756 (450) 4027 (380)
RTI-387 Me p-fluorophenyl 6.45 917 (546) >100K (9400)

3-Substituted-1,2,4-oxadiazole

Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.
Code X R DA NE 5HT
ααRTI-87 H 3-methyl-1,2,4-oxadiazole 204 36K 30K
βαRTI-119 H 3-methyl-1,2,4-oxadiazole 167 7K 41K
αβRTI-124  H 3-methyl-1,2,4-oxadiazole 1028 71K 33K
RTI-125  Cl 3-methyl-1,2,4-oxadiazole 4.05 363 2584
ββRTI-126  H 3-methyl-1,2,4-oxadiazole 100 7876 3824
RTI-130  Cl 3-phenyl-1,2,4-oxadiazole 1.62 245 195
RTI-141 Cl 3-(p-anisoyl)-1,2,4-oxadiazole 1.81 835 357
RTI-143 Cl 3-(p-chlorophenyl)-1,2,4-oxadiazole 4.1 4069 404
RTI-144 Cl 3-(p-bromophenyl)-1,2,4-oxadiazole 3.44 1825 106
βRTI-151  Me 3-phenyl-1,2,4-oxadiazole 2.33 60 1074
αRTI-152 Me 3-phenyl-1,2,4-oxadiazole 494 1995
RTI-154 Cl 3-isopropyl-1,2,4-oxadiazole 6 135 3460
RTI-155 Cl 3-cyclopropyl-1,2,4-oxadiazole 3.41 177 4362


N-methylphenyltropanes with 1R β,β stereochemistry.
Code X 2 Group DA NE 5HT
RTI-157 Me tetrazole 1557 >37K >43K
RTI-163  Cl tetrazole 911 5456
RTI-178  Me 5-phenyl-oxazol-2-yl 35.4 677 1699
RTI-188  Cl 5-phenyl-1,3,4-oxadiazol-2-yl 12.6 930 3304
RTI-189  Cl 5-phenyl-oxazol-2-yl 19.7 496 1116
RTI-194  Me 5-methyl-1,3,4-oxadiazol-2-yl 4.45 253 4885
RTI-195  Me 5-phenyl-1,3,4-oxadiazol-2-yl 47.5 1310 >22,000
RTI-199  Me 5-phenyl-1,3,4-thiadiazol-2-yl 35.9 >24,000 >51,000
RTI-200  Cl 5-phenyl-1,3,4-thiadiazol-2-yl 15.3 4142 >18,000
RTI-202  Cl benzothiazol-2-yl 1.37 403 1119
RTI-219  Cl 5-phenylthiazol-2-yl 5.71 8516 10,342
RTI-262 Cl
RTI-370  Me 3-(p-cresyl)isoxazol-5-yl 8.74 6980 >100K
RTI-371
RTI-371
3β--2β-[3-isoxazol-5-yl]tropane is a phenyltropane derived drug which acts as a potent and selective dopamine reuptake inhibitor in vitro, yet unusually for this class of compound, both RTI-371 and the closely related compound RTI-370 failed to produce locomotor stimulation in mice...

 
Cl 3-(p-chlorophenyl)isoxazol-5-yl 13 >100K >100K
RTI-436 Me
3.09 1960 (1181) 335 (31)
RTI-470 Cl o-Cl-benzothiazol-2-yl 0.094 1590 (994) 1080 (98)
RTI-451 Me benzothiazol-2-yl 1.53 476 (287) 7120 (647)


N-alkyl

Compound X 2 Group config 8 DAT SERT NET
FP-β-CPPIT  Cl 3'-phenylisoxazol-5'-yl β,β NCH2CH2CH2F
FE-β-CPPIT  Cl (3'-phenylisoxazol-5'-yl) β,β NCH2CH2F
Altropane
Altropane
Altropane, is a phenyltropane derivative which acts as a potent dopamine reuptake inhibitor and long-acting stimulant drug...

 
F CO2Me β,β NCH2CH=CHF
RTI-310  I CO2Me β,β N-Prn 1.17
RTI-311  I CO2Me β,β NCH2CH=CH2 1.79
RTI-312  I CO2Me β,β NBun 0.76
RTI-313  I CO2Me β,β NCH2CH2CH2F 1.67
Ioflupane
Ioflupane
Ioflupane is the International Nonproprietary Name of a phenyltropane compound which is a neuro-imaging radiopharmaceutical drug, used by nuclear medicine physicians for the diagnosis of Parkinson's disease and the differential diagnosis of Parkinson's disease over other disorders presenting...

 
¹²³I CO2Me β,β NCH2CH2CH2F
RTI-251  Cl CO2Me β,β NCH2CO2Et 1.93 10.1 114
RTI-252  Cl CO2Me β,β NCH2CH2CO2Et 2.56 35.2 125
RTI-242  Cl β,β (bridged) -C(O)CH(CO2Me)CH2N 7.67 227 510


Bi- and tri-cyclic aza compounds and their uses

N-replaced (S,O,C)

{| class="wikitable"
| Compound || X || 2 Group || config || 8 || DA||5-HT||NE
|-
| Tropoxane
Tropoxane
Tropoxane is an aryloxytropane derivative drug developed by Organix Inc, which acts as a stimulant and potent dopamine and serotonin reuptake inhibitor. It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link , demonstrating that the amine nitrogen is...

 || Cl,Cl|| CO2Me ||(racemic) β,β || O ||3.3||6.5||No data
|}

Irreversible

Irreversible
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....

 (phenylisothiocyanate) binding ligand
RTI-76: 4-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate

Nortropanes (N-demethylated)

NS2359
NS2359
NS-2359 is a serotonin-norepinephrine-dopamine reuptake inhibitor. It was under development by GlaxoSmithKline as an antidepressant, but was discontinued in 2009 when phase II clinical trials turned up disappointing results and did not support further effort by the company...

 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...

 binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant. Of course, this is not always the case. For an interesting exception to this trend, see the Taxil
RTI-274
RTI-274, or 2β--3α-nortropane is a phenyltropane homologue of paroxetine developed by the group led by F Ivy Carroll in the 1990s.-Introduction:...

 document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues which have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.

Selected ββ Nortropanes
Code X DA 5HT NE
RTI-142  F 4.39 68.6 18.8
RTI-98  I 0.69 0.36 11.0
RTI-110  Cl 0.62 4.13 5.45
RTI-173  Et 49.9 8.13 122




































































N-demethylating various archetypal '4HC-Tropanes.

X [3H]Paroxetine [3H]WIN 35,428 [3H]Nisoxetine
Ethyl
Ethyl
Ethyl may refer to:* Ethyl group, a functional group in organic chemistry* Ethyl Corporation, a fuel additive company* Ethanol, also known as ethyl alcohol* Cold Ethyl, a rock band founded by Nicke Andersson...

28.4 → 8.13 55 → 49.9 4,029 → 122
vinyl
Vinyl
A vinyl compound is any organic compound that contains a vinyl group ,which are derivatives of ethene, CH2=CH2, with one hydrogen atom replaced with some other group...

9.5 → 2.25 1.24 → 1.73 78 → 14.9
Ethynyl
Ethynyl
In organic chemistry, the term ethynyl designates*An ethynyl group .*The ethynyl radical ....

4.4 → 1.59 1.2 → 1.24 83.2 → 21.8
1-Propyl 70.4 → 26 68.5 → 212 3,920 → 532
t-propenyl
Propenyl
Propenyl is a chemical radical of propene .Propenyl groups bind water molecules inside rocks. The amount of water trapped in a rock varies by composition.-References:http://www.biology-online.org/dictionary/Propenyl...

11.4 → 1.3 5.29 → 28.6 1,590 → 54
c-propenyl 7.09 → 1.15 15 → 31.6 2,800 → 147
Allyl
Allyl
An allyl group is a substituent with the structural formula H2C=CH-CH2R, where R is the connection to the rest of the molecule. It is made up of a methylene , attached to a vinyl group . The name is derived from the Latin word for garlic, Allium sativum. Theodor Wertheim isolated an allyl...

28.4 → 6.2 32.8 → 56.5 2,480 → 89.7
1-Propynyl
Propynyl
In chemistry, propynyl is an propyl functional group bearing a triple bond. 2-Propynyl is known as propargyl group with the structure of HC≡C−CH2 and 1-propynyl group has the structure of CH3-C≡C-....

15.7 → 3.16 2.37 → 6.11 820 → 116
i-Propyl 191 → 15.1 597 → 310 75,000 → ?
2-Propenyl
Propenyl
Propenyl is a chemical radical of propene .Propenyl groups bind water molecules inside rocks. The amount of water trapped in a rock varies by composition.-References:http://www.biology-online.org/dictionary/Propenyl...

3.13 → 0.6 14.4 → 23 1,330? → 144


>
N-Demethylating phenyltropanes to find a NRI
Isomer 4' 3' NE DA 5HT
β,β Me H 60 → 7.2 1.7 → 0.84 240 → 135
β,β F H 835 → 18.8 15.7 → 4.4 760 → 68.6
β,β Cl H 37 → 5.45 1.12 → 0.62 45 → 4.13
β,α Me H 270 → 9 10.2 → 33.6 4250 → 500
β,α F H 1200 → 9.8 21 → 32.6 5060 → 92.4
β,α Cl H 60 → 5.41 2.4 → 3.1 998 → 53.3
β,α F Me 148 → 4.23 13.7 → 9.38 1161 → 69.8
β,α Me F 44.7 → 0.86 7.38 → 9 1150 → 97.4


"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine
Manifaxine
Manifaxine is a drug developed by GlaxoSmithKline through structural modification of radafaxine, the active metabolite of bupropion. It acts as a norepinephrine-dopamine reuptake inhibitor...

, and reboxetine
Reboxetine
Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia . Its mesylate salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra...

 as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).

Select annotations of above

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.

Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. , , , and .

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug which is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...

 binding affinity.

Sister substances

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...

 class (a category that includes methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...

) or benztropine
Benztropine
Benzatropine , also known as benztropine , is an anticholinergic marketed under the trade name Cogentin which is used in the treatment of Parkinson's disease, parkinsonism, akathisia, and dystonia.- Indications :...

 class (such as Difluoropine
Difluoropine
--2β-Carbomethoxy-3α-tropane is a stimulant drug synthesised from tropinone, which acts as a potent and selective dopamine reuptake inhibitor...

: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRI
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...

s are far removed from being in the phenyltropane structural family, such as Benocyclidine
Benocyclidine
Benocyclidine , or benzothiophenylcyclohexylpiperidine , is a psychoactive drug and research chemical of the arylcyclohexylamine and piperidine chemical classes. It acts a potent and selective dopamine reuptake inhibitor and a stimulant...

 or Vanoxerine
Vanoxerine
Vanoxerine is a piperazine derivative which is a potent and selective DRI. GBR-12909 binds to the target site on the DAT ~ 500 times more strongly than cocaine, but simultaneously inhibits the release of dopamine...

.

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK